Multi-slice cerebral blood flow imaging with continuous arterial spin labeling mri

ABSTRACT

This invention is a method for multi-slice CBF imaging using continuous arterial spin labeling (CASL) with an amplitude modulated control which is both highly effective at controlling for off resonance effects, and efficient at doubly inverting inflow spins, thus retaining the signal advantages of CASL versus pulsed ASL techniques.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/198,581 filed Aug. 5, 2005, entitled “MULTI-SLICE CEREBRAL BLOOD FLOWIMAGING WITH CONTINUOUS ARTERIAL SPIN LABELING MRI”, which is acontinuation of U.S. application Ser. No. 09/673,049 filed Oct. 10, 2000which issued as U.S. Pat. No. 6,980,845 on Dec. 27, 2005, which is thenational phase of PCT Application No. PCT/US99/08087 filed Apr. 13,1999, which claims benefit of U.S. Provisional Application Ser. No.60/081,506 filed Apr. 13, 1998, each of which is hereby incorporated byreference, in its entirety.

GOVERNMENT SUPPORT

This invention was supported by funds from the U.S. Government (NationalInstitutes of Health grants NS01668, P30-MH93880, and P50-NS08803) andthe U.S. Government may therefore have certain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a technique for imaging regionalcerebral blood flow (CBF) noninvasively using MRI with radio frequencyarterial spin labeling and, more particularly, to a labeling techniquewhich permits extension of this technique to a multi-slice examination.

2. Description of the Prior Art

The measurement of regional cerebral blood flow (CBF) is known toprovide useful information both about cerebrovascular sufficiency andabout regional brain metabolism because resting CBF and tissuemetabolism are often strongly coupled. CBF imaging with Single PhotonComputed Tomography (SPECT), Positron Emission Tomography (PET) andXenon enhanced CT have been used to evaluate a multitude of cerebraldisorders including stroke, dementia, epilepsy, trauma and neoplasms.PET imaging of CBF has also been an important tool for mapping taskinduced brain activity in normal and pathologic states. However, formost central nervous system disorders, Magnetic Resonance Imaging(MRI)provides the greatest sensitivity to structural abnormalities. A robustMRI based method for clinical imaging of CBF would allow both ananatomical and a functional assessment within the same examination. Inaddition to providing direct structure-function correlation, the higherspatial resolution of MRI as compared to nuclear medicine methods willlead to better image quality.

MRI of CBF can be performed either with intravascular contrast agents orby Arterial Spin Labeling (ASL). As known to those skilled in the art,instead of using an exogenous tracer, ASL electromagnetically labelswater proton spins in the feeding arteries before they flow into thetissue. ASL is attractive since it can reduce the risk, complexity, andcost of a study. It is also more readily quantified and repeated thancontrast agent methods.

Arterial Spin Labeling (ASL) techniques can be crudely divided intopulsed inversion techniques, such as EPISTAR, FAIR and other variants,and techniques which employ continuous arterial spin labeling (CASL).CASL produces more than twice the signal of pulsed techniques.Unfortunately, with both methods, multi-slice imaging is complicated byeffects of the electromagnetic labeling on the image intensity, as wellas the relatively long time required for blood to flow from the arteriesinto the thick slab of tissue to be imaged.

The ASL approach to MRI of CBF offers the potential for completelynon-invasive, quantitative imaging of an important physiologic anddiagnostic quantity; however, practical implementations of ASL in humanshave typically suffered from systematic errors and artifacts which canonly be corrected one slice at a time and which have thus limited itsapplicability. Recently, the use of fast imaging methods and anincreased understanding of the factors affecting quantification of CBFhave led to the acquisition of single-slice CBF images of good qualitysuch that clinical and research applications can be explored.Unfortunately, most applications require greater slice coverage but theserial acquisition of many slices can be prohibitively time consuming.However, improved Radio Frequency (RF) pulse shapes and sequence designhas made multi-slice pulsed ASL techniques feasible and multi-sliceperfusion imaging more practical for diagnosis.

Accordingly, a method is desired which makes possible multi-sliceimaging of CBF with good signal-to-noise ratio and arbitrary anglesbetween imaging and labeling planes. The present invention is designedto meet this need in the art.

SUMMARY OF THE INVENTION

The present invention relates to a method for generating two sets ofimages which are identical except for the effects of blood flowing intothe imaged slices. Subtraction of the two images can provide images ofblood flowing in large vessels, sometimes referred to as angiograms, orperfusion, sometimes referred to as tissue specific blood flow,depending upon the timing of the imaging sequence. In particular, thepresent invention relates to the use of amplitude modulated RFirradiation prior to the acquisition of one set of images, hereafterreferred to as the control images, and the use of unmodulated RFirradiation prior to the acquisition of the second set of images,hereafter referred to as the labeled images. It is known in the priorart that constant RF irradiation, in combination with a magnetic fieldgradient, can change the MR signal of flowing blood from positive tonegative. The present invention employs the amplitude modulated RFirradiation prior to the control image acquisition to mimic all theblood flow unrelated effects of the constant RF irradiation whileleaving the blood signal positive. While prior art techniques for thecontrol image were only effective in a single thin slice at a particularangular orientation or required a second RF coil, the amplitudemodulated control approach of the invention is effective for any number,orientation, and thickness of slices.

In particular, the invention relates to a method for imaging blood flowinto a sample such as a tissue sample or a large blood vessel. Apreferred embodiment of the inventive method comprises the steps of:

perturbing arterial spins of blood flowing into the sample by applying aconstant RF irradiation together with a magnetic field gradient;

acquiring a first image of the sample;

applying amplitude modulated RF irradiation with a magnetic fieldgradient which, together, mimic the effects of constant RF radiationunrelated to blood flow;

acquiring a second image of the sample; and

generating a difference signal based on the first image and the secondimage that represents a blood flow image of blood flowing into thesample.

In a preferred embodiment of the invention, the first image is acquiredafter a delay period by detecting a magnetic resonance signal reflectedoff of the sample. The delay period is set either to allow the bloodhaving the perturbed spins to flow into the tissue before the images arecaptured (i.e., to capture a perfusion image), or to ensure that theimages are captured while the blood is still in the blood vessel (i.e.,to capture a large vessel blood flow image). The second image isacquired in a similar fashion shortly after the amplitude modulated RFirradiation is applied. The analog magnetic resonance signals arepreferably digitized and processed to measure blood flow via knowntechniques.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other novel features and advantages of the inventionwill become more apparent and more readily appreciated by those skilledin the art after consideration of the following description inconjunction with the associated drawings, of which:

FIG. 1A illustrates a single slice experiment in which the controllabeled images are acquired with labeling applied at an equal distancedistal to the slice (solid line) to compensate for the spatiallydependent off resonance effects.

FIG. 1B illustrates the amplitude modulated irradiation technique of theinvention whereby two inversion planes are created close to the originallabeling plane.

FIG. 2 illustrates a pulse sequence timing diagram for the entiresequence used to amplitude modulate the RF pulse in accordance with themethod of the invention.

FIG. 3 illustrates the percent difference between labeling and controlimages in a phantom as a function of frequency.

FIG. 4 illustrates coronal images acquired in a human study with thelabel and control respectively placed at the ponto-medullary junctionand 2 cm above the brain as indicated on the sagittal T1 images on theleft of the figure.

FIG. 5 illustrates a plot of the residual subtraction errors caused byimperfect matching of off-resonance saturation.

FIG. 6 illustrates the efficiency of spin labeling with amplitudemodulated control as a function of modulation frequency relative to asingle slice labeling.

FIG. 7 illustrates echoplanar images from eight axial slices (top row)used to generate CBF sensitive images (second row) as well as acquiredT1 maps (third row) used to generate quantitative images of CBF (bottomrow).

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

A preferred embodiment of the invention will now be described in detailwith reference to FIGS. 1-7. Those skilled in the art will appreciatethat the description given herein with respect to those figures is forexemplary purposes only and is not intended in any way to limit thescope of the invention. All questions regarding the scope of theinvention may be resolved by referring to the appended claims.

Materials and Methods Amplitude Modulated Control

Continuous application of off resonance RF power causes saturation ofimage intensity due to the finite width of the water line and thetransfer of saturated magnetization from water molecules adjacent tomacromolecules, which have much broader lines. The off-resonanceinversion power applied in CASL usually causes such saturation and itspresence complicates CBF imaging since the off-resonance effects may belarge compared to the effects of blood flow. An approach to eliminatingthis saturation is the use of a second small RF coil for labeling thatis far enough from the imaged slice that the off-resonance power isnegligible. This method has been previously used successfully to obtainmulti-slice CBF images in a rat brain but it requires special RFhardware and a favorable geometry for the labeling which limits itsapplicability. The alternative is to control for the saturation. SinceASL CBF imaging relies on the subtraction of the labeled image from areference image obtained without labeling, achieving equal off-resonancesaturation in the reference image will control for the saturationeffect.

FIG. 1 illustrates control methods for CASL imaging of CBF. RFirradiation used to label inflowing blood as it crosses the labelingplane (dashed line) also causes direct effects on image intensity thatvary with distance from the labeling plane. The established method ofcontrolling for off resonance saturation with a single RF coil was toapply an inversion distal to the slice during the control image, asillustrated in FIG. 1A. FIG. 1A illustrates a single slice experiment inwhich the control labeled images are acquired with labeling applied atan equal distance distal to the slice (solid line) to compensate for thespatially dependent off resonance effects. If there are no significantbackground magnetic field gradients in the sample (e.g., the tissue orblood vessel), the off-resonance saturation is symmetric in frequency,and the labeling and control inversion are parallel to and equidistantto the image slice, then the control image will experience equaloff-resonance saturation. However, the requirement that the labeling andcontrol inversion planes be equidistant to and parallel to the imageslice restricts the geometry of ASL CBF images and is not readilyextended to a multi-slice examination. To overcome these limitations, analternative control irradiation which mimics the frequency dependentoff-resonance effects of the labeling irradiation is required.

Thus, in the method of the invention, applying an amplitude modulatedform of the labeling RF irradiation for the control was evaluated. Inparticular, it was observed that when a constant RF irradiation at afixed frequency, f₀, is multiplied by a sine wave at frequency f₁, thesignal produced is mathematically identical to continuous irradiation attwo different frequencies, f₀+f₁ and f₀−f₁. If applied in the presenceof a magnetic field gradient, each would separately perturb, such as byadiabatic inversion, inflowing arterial spins. When performedsimultaneously, the combined effect is complicated because the equationsgoverning spin evolution are not linear in the applied RF. However, thenature of resonance suggests that the effect of the first inversion onspins located near the second inversion plane should be small as long asthe frequency spacing between the planes is large. In this case, thespins will be inverted twice after flowing through the two inversionplanes, as illustrated in FIG. 1B. In FIG. 1B, the amplitude modulatedirradiation creates two inversion planes (solid lines) close to theoriginal labeling plane. Ideally, the inflowing spins are inverted twiceas they flow through the planes producing no net effect on arteriallabeling while the spatially dependent off resonance effects of the RFirradiation are precisely reproduced. Double inversion produces no neteffect, so spins would not be labeled by the amplitude modulatedcontrol. Because the average power and center frequency of the amplitudemodulated control are identical to the labeling RF irradiation, theoff-resonance effects of the control are nearly identical to those ofthe labeling.

The performance of amplitude modulation of the RF irradiation as acontrol will depend on how perfectly the spins are doubly inverted, andon how well the off-resonance saturation of the labeling irradiation ismatched. If the spins are partially labeled by the amplitude modulatedcontrol, then the difference between the labeled and control images willdecrease. This can be thought of as a loss of efficiency for labeling ofblood flow. If the control does not perfectly match the off-resonancesaturation of the labeling, then a difference between the images willoccur even in the absence of blood flow. This would represent asystematic error in the blood flow measurement. Both of these propertiesof the control were assessed experimentally as described below.

Imaging

All studies using the techniques of the invention were performed on a1.5 Tesla GE SIGNA clinical scanner equipped with a prototype gradientsystem for echoplanar imaging. Gradient echo echoplanar images wereobtained using a field of view of 24 cm along the frequency encodingdirection and 15 cm for the phase direction and an acquisition matrix of64×40. An acquisition bandwidth of ±62.5 kHz allowed an effective TE of22 ms and an image acquisition time of 45 ms. Multi-slice imageacquisition was performed without pausing between slices so that 8slices could be acquired in less than 400 ms. Slice thickness rangedbetween 6 and 10 mm and interslice gaps of 2 mm between slices were usedto minimize potential interference between slices.

Spin labeling was performed for single slice CBF imaging except for theamplitude modulated control and the acquisition of more than one slice.Specifically, a TR of 4 s, temporal interleaving of labeled and controlimages, and a post-labeling delay were employed. The post-labeling delayreduced the sensitivity of the CBF image to the transit time from thelabeling plane, attenuated the signal from intraluminal arterial spins,and decreased the off-resonance saturation of the image intensity by thelabeling RF. The post-labeling delay also allows time for all of thelabeled blood to enter the tissue before imaging so that saturation oflabeled spins by the imaging excitation pulses need not be considered.The duration of the labeling irradiation was determined by thepost-labeling delay, the imaging time and TR. For a post-labeling delayof 1.2 s, the irradiation was applied for 2.3 s. A pulse sequence timingdiagram for the entire sequence is shown in FIG. 2. In the timingdiagram of FIG. 2, labeling RF signals and gradients are applied duringthe labeling period. Rapid gradient echo echoplanar imaging was used toacquire images from the 8 slices.

In addition to the CBF scan, multi-slice versions of the conventionalechoplanar T1 mapping scans were performed. The T1 maps are necessaryfor quantification of the CBF images. Unlike in the single-sliceimplementation, it was necessary to leave the labeling gradient onduring T1 mapping to accurately measure the T1 shortening effect of theoff-resonance saturation. In all other ways the protocol was identical.The entire T1 mapping protocol required 3 minutes for all slices.

All raw echo amplitudes were saved and transferred to a workstation forreconstructing the images. A correction for image distortion andalternate k-space line errors was performed on each image using dataacquired during a phase encoded reference scan. As known to thoseskilled in the art, the correction for distortion involves themeasurement of magnetic field nonuniformity throughout the image. Aside-effect of this correction is that image regions where insufficientMR signal is present to accurately measure the magnetic field are set tozero. The magnitude images were then averaged and the CBF weightedimages were calculated by subtraction of labeled images from the controlimages. An algorithm to remove subtle motion artifacts from the imageswas performed on the individual images prior to averaging for moreaccurate evaluation of the performance of the control.

Phantom Studies

Prior to evaluation in human subjects, the sequence was tested andcalibrated on a uniform phantom consisting of 2% agarose by weight indistilled H₂O. Such a phantom with significant magnetization transferwas necessary to fully test the control. The magnetization transferproperties of agarose are well studied but considerably different frommost human tissues. Since it was desired that the control would beaccurate across a wide range of tissue types, the agarose phantom wasselected since it served as an extreme case.

The phantom consisted of a cylindrical plastic container, 10 cm indiameter and 20 cm long, filled with the gelatinous mixture. The phantomwas placed in the standard head coil of the scanner with the axisparallel to the axis of the magnet. Single-slice images employing theCBF labeling strategy were acquired in a plane perpendicular to the axisof the phantom. A labeling RF irradiation of 35 mG and a labelinggradient of 0.25 G/cm applied along the frequency direction of the imagewere used. Images were acquired with amplitude modulation frequencies of125, 250 and 500 Hz. Off-resonance saturation was analyzed by averagingthe images across the phase direction so that plots of off-resonancesaturation as a function of frequency could be generated.

During evaluation of the sequence, it was found that weak saturation ofsignal at the labeling plane occurred even when the RF amplitude was setto zero in software. This indicated that a small amount of RF wasleaking past the modulator. The saturation could be eliminated bysetting the RF amplitude to a small negative value corresponding to 2%of the RF amplitude used for labeling. A constant value of 2% of thesignal amplitude was subtracted from the software values of all of thelabeling related RF amplitudes to compensate for this carrier leakage.Failure to correct for this leakage would cause systematic error in theCBF measurement. Since the leakage is a subject independent phenomenon,it can be calibrated with phantom measurements and need never bemeasured in subjects.

Human Studies

Three different human studies were performed. In one study, theamplitude modulated control method was tested for systematic offset dueto imperfect matching of the off-resonance saturation for label andcontrol. Two subjects were scanned with a control modulation frequencyof 250 Hz, an RF irradiation amplitude of 35 mG, a post-labeling delayof 1.2 s, and a 0.25 G/cm labeling gradient. Images from eight 8 mmthick slices were obtained from both subjects when the labeling wasapplied to the carotid and vertebral arteries at the ponto-medullaryjunction, to generate CBF images, and also when the labeling was applieddistal to the imaging slice at the top of the brain, which shouldproduce no flow-related signal in the absence of systematic error. Oneof the subjects was scanned in the axial plane while the other wasscanned in the coronal plane to emphasize the flexibility of slicegeometry made possible by the amplitude modulated control technique ofthe invention.

In a second study, the efficiency of the multi-slice CBF measurement wascompared with the single slice method. CBF images were acquired in asingle axial slice through the basal ganglia and thalamus in ninesubjects. Images were acquired with both the single slice method, wherethe control is labeling distal to the slice, and the multi-slice method.All subjects were studied with a 0.25 G/cm labeling gradient, an RFirradiation amplitude of 35 mG, a control modulation frequency of 250Hz, a post-labeling delay of 1.2 s, and a labeling plane offset ofbetween 4 and 8 cm from the slice. Between 15 and 45 difference imageswere averaged for each subject. In three of these subjects the singleslice and multi-slice methods were also compared at RF amplitudes of 30and 20 mG. In three other subjects, the methods were also compared withmodulation frequencies of 62.5 Hz, 100 Hz, 125 Hz, 200 Hz and 500 Hz.

In the final human study, multi-slice CBF images and T1 maps wereobtained with 250 Hz modulation and 35 mG RF amplitude in four subjectsfor quantitative analysis of CBF using prior art methods. The entire CBFimaging sequence required 9 minutes including T1 mapping and 45 averagesof tagged and control images. The multi-slice labeling efficiencymeasured in the first study was used for quantification.

Results Phantom Study

Matching of frequency dependent off-resonance saturation effects betweenthe labeling and amplitude modulated control was excellent at all threefrequencies, as shown in FIG. 3, where the percent difference betweenlabeling and control images in the phantom is shown as a function offrequency. Though both types of irradiation produced off-resonancesaturation of greater than 15% of the unsaturated signal, the differencebetween the two was less than 0.1% except very close to the labelingplane. The frequency at which the difference between the labeled andcontrol frequencies became significant was smaller for lower frequencyamplitude modulation. This suggests that labeling can be performedcloser to the most inferior region to be imaged when a slower amplitudemodulation is used.

Human Studies

Excellent matching between the labeling and control off-resonancesaturation in the phantom was also reproduced in the in vivo studies.FIG. 4 shows the coronal images acquired with label and control placedat the ponto-medullary junction and 2 cm above the brain as indicated onthe sagittal T1 images on the left of the figure. Multi-slice differenceimages acquired with the proximal labeling (top right) demonstratesignal from CBF. Images acquired with the distal labeling (bottom right)show no significant signal. In other words, while the scans with theponto-medullary junction label show strong perfusion signal in alldistal regions of the brain, hose with the label above the brain show nosignificant signal.

To further quantify residual subtraction errors caused by imperfectmatching of off-resonance saturation, the image intensity was averagedacross the slice and phase directions, similar to the phantom analysis,and the results were plotted in FIG. 5. In FIG. 5, the averagedifference signal was obtained by averaging the images of FIG. 3 acrossthe anterior-posterior and right-left directions. Distance from thelabeling plane was converted into frequency offset for plotting. Asshown, proximal labeling at the ponto-medullary junction produced asmall but very significant change in the image intensity due to CBF,while distal labeling above the brain produced no significant signalchange consistent with negligible off-resonance errors for offsetfrequencies above 2 kHz.

While perfusion produces a signal change of under one percent in theproximal labeled scans, residual subtraction error for frequencies above2 kHz as measured by the distal labeled scans is consistent with noiseand is always less than 0.05 percent. The average of the subtractionsignal across frequency from 2 to 10 kHz is less than 0.007 percent ofthe control image intensity. Since the CBF images were acquired in aplane perpendicular to the labeling plane, their uniformity is also adirect indicator of the accuracy of the control. Errors in subtractionare apparent in the perfusion signal of FIG. 5 very near the labelingplane at offset frequencies below 2 kHz. The subtraction error producesa shift to a negative signal consistent with the phantom results of FIG.3.

The mean efficiency ratio of the multi-slice and single slice methodswas 61.6% ±6.7% across the nine subjects when a modulation frequency of250 Hz was used. This efficiency was found to drop rapidly when theamplitude of the RF was lowered; the efficiency at 30 mG was 58% and at20 mG it was only 35%. As shown in FIG. 6, the efficiency of spinlabeling with amplitude modulated control as a function of modulationfrequency relative to a single slice labeling with 36 mG amplitudeirradiation improved to 75% when the modulation frequency was lowered.This suggests that a modulation frequency of 62.5 Hz is more desirablethan 250 Hz.

Quantification of the CBF images was next performed using prior artmethods for single slice imaging. The average of the labeled images wasfirst subtracted from the average of the control images and then dividedby the intensity of an image obtained in the absence of off resonancesaturation. This ratio was then multiplied by a calibration factor whichis a function of the calculated T1 images, the transit times to thetissue from the labeling plane, and the post-labeling delay for eachslice. Because the transit time to the tissue was not measured, anassumed value of 1.5 s was employed for quantification. The longpost-labeling delay minimized the sensitivity of the calibration factorto differences between the assumed and actual transit time. The imageswere corrected for inefficiency of labeling by dividing by an efficiencyof 58.5%. This value was based on an efficiency of 95% for the singleslice experiment and the measured ratio of multi-slice to single sliceefficiency of 61.6%. Calculated images from one of the subjects aredisplayed in FIG. 7. In FIG. 7, echoplanar images from eight axialslices (top row) were used to generate CBF sensitive images (secondrow). Using the T1 maps also acquired (third row), quantitative imagesof CBF were generated (bottom row).

These images are not corrected for spatial variations in the blood-brainpartition coefficient. Quantitative CBF values were derived bysegmenting the tissue into gray and white matter based on the T1 mapsand using a partition coefficient of 0.98 for gray matter and 0.82 forwhite matter. The measured CBF values are consistent with values forquantitative cerebral blood flow (ml 100 g⁻¹ min-1) obtained previouslyusing single slice methods and with other measurements of CBF, asrepresented for four normal volunteers in Table 1.

TABLE 1 Gray White Subject Age Sex Matter Matter Mean 1 24 M 70.5 27.153.7 2 25 M 71.4 28.5 54.8 3 32 M 61.7 32.5 50.4 4 21 F 85.9 49.7 71.9Mean 25.5 ± 5 72.4 ± 10 34.5 ± 10 57.7 ± 10

Discussion

The invention relates to a method for multi-slice CBF imaging using CASLwith an amplitude modulated control. This control strategy is bothhighly effective at controlling for off-resonance effects and efficientat doubly inverting inflowing spins, thus retaining the signaladvantages of CASL versus pulsed ASL techniques. The method is readilyimplemented using standard hardware, is effective in both gray and whitematter, and allows flexible selection of the imaging and labelingplanes. Because the control method is applied at the same location asthe labeling and gives equal effect across a wide range of frequencies,there should be no errors associated with static magnetic fieldinhomogeneity or asymmetry in the off-resonance spectrum. The labelingmethod is therefore highly desirable even for single-slice CBF imagingapplications. This approach should also be applicable to blood flowmeasurements in organs other than the brain. Also, although the abovestudies were carried out in eight slices, the number of slices islimited only by the image acquisition time and T1 of blood and tissue.

The highest efficiency was measured for the lowest modulation frequencyin the study, 62.5 Hz, which was contrary to the inventor's expectationthat the two inversion planes would start to interfere as they becamecloser. The inventor has implemented numerical simulations of thecontrol using methods similar to those published for single slicelabeling. These simulations suggest that inefficiency results primarilyfrom non-linear interactions between the two inversion planes ratherthan T1 decay between the two planes.

The use of gradient echo echoplanar imaging with a moderately long TE inthis study caused signal loss in parts of the inferior frontal andtemporal lobes because of nonuniform magnetic fields near bones andsinuses. Spin echo echoplanar was avoided because it would haveincreased the duration of image acquisition. Fractional k-spaceacquisition could have enabled much shorter effective TE gradient echoor spin echo echoplanar images with comparable or shorter acquisitiontimes to the sequence. If necessary for image speed or quality, otherimaging methods such as interleaved echoplanar or RARE might be employedas long as they do not unacceptably increase the motion artifact.

Spin labeled perfusion images clearly reflect CBF and its spatial andtemporal variation but further work is required to test and validate thequantitative values obtained with the technique of the invention.

Those skilled in the art will appreciate that the extension of CASL CBFimaging to a multi-slice modality in accordance with the techniques ofthe invention overcomes a major obstacle to clinical applications. Thetechniques of the invention have already been successfully applied inpatients with cerebrovascular disease. CBF measurements using thisapproach are also likely to provide a sensitive and quantitative measureof cerebrovascular reserve when carried out in conjunction withacetazolamide administration or CO₂ inhalation. Numerous other potentialclinical applications can be envisioned, including the differentialdiagnosis of dementing disorders and cerebral neoplasms. In addition,quantitative CBF measurements have applications to clinical and basicneuroscience, for imaging regional CBF changes during sensorimotor orcognitive tasks or following pharmacological challenges, and forpopulation-based studies of changes in regional CBF and metabolism.

Those skilled in the art will appreciate that numerous othermodifications to the invention are possible within the scope of theinvention. Accordingly, the scope of the invention is not intended to belimited to the preferred embodiments described above, but only by anyappended claims.

1-4. (canceled)
 5. A method for generating a blood flow image, themethod comprising: perturbing arterial spins of blood flowing into asample by applying a constant RF irradiation together with a magneticfield gradient; waiting a transit delay period before acquiring a firstimage of the sample, wherein the transit delay period is of a durationthat allows for acquisition of the first image while the blood havingperturbed arterial spins is exhibiting a desired flow characteristicwithin the sample; acquiring a first image of the sample; applyingamplitude modulated RF irradiation with a magnetic field gradient which,together, mimic the effects of constant RF radiation; acquiring a secondimage of the sample; generating a blood flow image based on a differencebetween the first image and the second image.
 6. The method of claim 5,wherein the sample comprises a blood vessel and a tissue portion, andthe transit delay period is of a duration that allows for acquisition ofthe first image while the blood having perturbed arterial spins flows inthe blood vessel.
 7. The method of claim 5, wherein the sample comprisesa blood vessel and a tissue portion, and the transit delay period is ofa duration that allows for acquisition of the first image while theblood having perturbed arterial spins flows in the tissue portion of thesample.